Cholera has reemerged as a global killer with the world witnessing an unprecedented rise in cholera infection and transmission over the past two decades. The causative agent of cholera is Vibrio cholera, a natural inhabitant of many types of aquatic environments but is more prevalent in coastal ecosystems. Thus, a warmer global climate with increasingly variable precipitation patterns and accelerated sea level rise is likely to have wide-ranging effects on the outbreaks and transmission of this infectious disease. Most of these health effects are likely to occur where hydrologic, climatic, and ecological extremes and population vulnerability converge. The impact of variability and changes in climatic conditions in cholera prone regions of the world are not well understood. Extreme climatic events such as prolonged droughts, floods and major cyclones have been implicated with major cholera epidemics. Such extreme events are also likely to create unseen changes in the ecosystem and can potentially impact cholera bacteria. Existing literature suggests that significant uncertainly and knowledge gaps remain in attributing the expansion and resurgence of cholera to climate change for two reasons: (i) incomplete understanding of ecology of cholera within the context of climatic and hydrologic extremes and their manifestations on the epidemiology of cholera;and (ii) lack of long-term data sets as well as absence of mechanistic models that can link climate, hydrology, ecology, and epidemiology of cholera within a consistent framework. Three empirical observations suggest possible connections among climate change and variability with ecology, hydrology and microbiology of cholera: (a) if the current warming trends continue, extreme events are likely to be more frequent and intense;(b) almost all cholera outbreaks originate near the coastal areas;and (c) extreme weather and climate events are likely to have significant effects on the outbreak and transmission of cholera vibrio. Taken together, these three empirical observations motivate us to explore the above two broad and complex knowledge gaps by investigating the role of hydrology, ecology, and climate on the epidemiology of cholera using an integrated diagnostic (Section 3.2) and predictive (Section 3.3) framework. Within the diagnostic framework, the specific aim is to examine linkages among climatic, hydrologic and ecological extremes with cholera dynamics by focusing on four related objectives: (1) Quantify the role of freshwater discharge from the large river basins in altering the relationships and seasonality of sea surface temperature (SST) and phytoplankton;(2) Quantify the effects of hydrologic and climatic extremes on cholera dynamics for different regions;(3) Evaluate the influences of ENSO cycle on cholera dynamics;and (4) Examine the effects of sea-level changes on estuarine ecosystems and cholera dynamics. To develop an effective cholera adaptation strategy for a changing climate, the specific aim within the predictive framework is to provide estimates of disease burden and outcomes for different plausible scenarios. A cholera-climate prediction model (CCPM) will be developed by integrating existing knowledge, results from diagnostic analyses and three previously developed physical models (downscaled climate projections, hydrologic module, and ecosystem module).The proposed CCPM will integrate hydrological, ecological, microbiological and oceanic determinants of cholera occurrences and transmission. A key innovation is the first direct application of downscaled climate projections from an ensemble of climate model simulations within a predictive cholera-climate model for three different regions (South Asia, Sub-Saharan Africa, and Latin America) of the world. This collaborative initiative among Tufts University, University of Maryland, and an international partner - Institute of Water Modeling from Bangladesh -- integrates and builds on several decades of expanding interdisciplinary experience in ecology and microbiology of cholera, hydrology, remote sensing, climatology, hydrodynamic and ecosystem modeling. Once tested and validated, the proposed cholera tracking and prediction model will have the capabilities and functionalities to be useful for many regions of the world. PUBLIC HEALTH RELEVANCE: Effects of Climate Change on Cholera Dynamics and Prediction A warmer climate is likely to have wide-ranging effects on outbreaks and transmission of cholera in different parts of the world where hydrologic, climatic, and ecological extremes and population vulnerability converge. The Cholera-Climate Prediction Model (CCPM) developed through this project will integrate hydrological, ecological, microbiological and oceanic determinants of cholera occurrences and transmission. This is perhaps the first direct application of downscaled climate projections from an ensemble of climate model simulations within a CCPM for three different cholera prone regions of the world. Once tested and validated, the proposed CCPM will have the capabilities and functionalities to be useful for many regions of the world.